Replenishing urease in dialysis systems using urease pouches

ABSTRACT

An apparatus and method for replenishing urease in a sorbent cartridge for use in sorbent dialysis using urease pouches. The sorbent cartridge is configured to allow insertion of a urease pouch or injection of a urease solution into the sorbent cartridge containing a urease pouch. The sorbent module can also comprise other, rechargeable, sorbent materials for removing toxins other than urea from spent dialysate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/644,576 filed Mar. 11, 2015, which claims benefit of and priority toU.S. Provisional Application No. 62/077,169 filed Nov. 7, 2014, and U.S.Provisional Application No. 62/016,613 filed Jun. 24, 2014, and thedisclosures of each of the above-identified applications are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compositions and related methods forreplenishing urease in modules, sections, or compartments of a sorbentcartridge. The urease can be replenished by adding one or more ureasepouches containing urease of varying sizes and configurations to thesorbent cartridge, or by injecting a urease solution into a sorbentcartridge containing a urease pouch. The sorbent cartridge can bedivided into a first section and a second section wherein the firstsection of the sorbent cartridge can contain urease, which can be addedby the urease pouches of the present invention as needed before, during,or after dialysis and a second section can contain other sorbentmaterials excluding urease such as zirconium phosphate.

BACKGROUND

Urease is a water soluble enzyme used in dialysis to convert urea intoammonium ions and bicarbonate. Oftentimes, urease can be immobilizedelectrostatically, covalently, or by adsorption on an alumina or silicasubstrate inside a sorbent cartridge that is designed to be connected toa dialysis system. However, conventional immobilization of urease hasbeen associated with the disadvantages of low loading and leaching ofurease that can result in insufficient amounts of urease for dialysis.Moreover, conventional sorbent dialysis systems cannot replenish, i.e.,provide additional or specified amounts of urease, to the known sorbentcartridges or dialysis systems. The inability to add urease, and controlthe amount of urease added, to the sorbent system use can be problematicbecause the amount of urease required for a particular dialysis sessioncan vary. The amount of urease required for a dialysis session maydepend on a number of factors such as patient weight, urea load,dialysis time, etc. resulting in different rates and amounts of ureaserequired per session. Using more or less than the required amount ofurease for a particular dialysis session can translate into increasedexpenditures and waste from unused or overused urease as well as othersorbent materials contained in the sorbent cartridge.

Known sorbent dialysis cartridges and systems further cannot measure theamount of urease used during a particular session or even replenish oradd urease back to the sorbent cartridge or system during operation asneeded, should a session need additional quantities of urease or shouldadditional urease be needed in the case of faster fluid flow ratesthrough the sorbent cartridge. Sometimes, certain sorbent materials suchas alumina and zirconium phosphate can be recharged such that thesorbent material is put back into a condition for use in sorbent baseddialysis (see U.S. application Ser. No. 14/261,651). As such, knownsorbent systems cannot recharge some or all of the sorbent materials,some of which can be rechargeable components within the sorbentcartridge, without undesirable effects. For example, rechargingzirconium phosphate in the same sorbent cartridge in which urease isimmobilized on alumina can result in urease, which is bound to analumina layer, being stripped off the alumina. More generally,recharging certain rechargeable sorbent materials in known sorbentcartridges can sometimes have undesirable effects on other sorbentmaterials contained inside the same sorbent cartridge. Known systemscannot replenish such urease lost due to recharging of other sorbentmaterials, or add a specific amount of urease to a sorbent cartridge orsorbent system during operation.

As such, there is a need for systems, methods, components and devicesfor optimizing use of sorbent materials such as urease within a sorbentcartridge. The need extends to systems that can replenish urease in asorbent cartridge, and related systems, by either directly addingdiscrete amounts of urease or by continuously adding urease to thesorbent system by a delivery mechanism. The need includes a sorbentcartridge and related systems in which urease can be added on demand,continuously, and in specified, discrete amounts. The need extends toproviding urease at a specified time such as after, before, or during adialysis session. The need includes providing the urease while thesystem is operating or off-line. There is also a need for a modularsystem, such as a system of different sized urease pouches that containurease of different quantities that can be easily added to a sorbentcartridge and related systems. The need includes adding the desiredamounts of urease in a simple and convenient manner and in adjustableamounts. The need includes a sorbent cartridge having a section whereinan adjustable amount of urease can be added. There is also a need for asorbent cartridge having a section for containing adjustable amounts ofurease. The need includes a sorbent cartridge optionally having asection for containing one or more sorbent materials that can be in afixed amount. In general, the need can be broadly described asdynamically adding urease to sorbent cartridges and related dialysissystems. The need can include adjusting the amount of required ureasedepending on a measured amount of ammonia detected anywhere in thesystem or sorbent cartridge.

There is a further need for a closed sorbent cartridge capable ofreceiving an adjustable amount of urease, on demand. The need includesmethods for measuring, refilling, and/or replenishing urease during adialysis session. The methods and systems require a way for introducingurease in continuous or specified and/or discrete amounts. The methodsand systems may involve pre-set amounts of urease or dynamicallyadjustable amounts of urease. There is also a need for a system capableof replenishing urease that may be stripped out of the sorbent cartridgelost during maintenance or during a dialysis session.

SUMMARY OF THE INVENTION

The first aspect of the invention relates to a sorbent cartridge. In anyembodiment of the first aspect of the invention, the sorbent cartridgecan comprise a first section having a urease introducer configured toreceive urease via one or more urease pouch.

In any embodiment of the first aspect of the invention, the sorbentcartridge can comprise a second section configured to contain one ormore sorbent materials; and a fluid connection fluidly connecting thefirst section to at least one additional section. The at least oneadditional section can be described in any embodiment of the firstaspect of the invention as a second section. In any embodiment of thefirst aspect of the invention, the sorbent materials can berechargeable.

In any embodiment of the first aspect of the invention, the ureaseintroducer can be selected from any one of: a urease injection port influid communication with either the first section or an inlet of thesorbent cartridge; a urease tray slideably disposed on the firstsection; and a urease door disposed on an exterior side of the sorbentcartridge allowing access into an interior of the first section.

In any embodiment of the first aspect of the invention, the urease trayand interior of the first section can be adapted to receive either aurease pouch containing urease or solid urease.

In any embodiment of the first aspect of the invention, the urease pouchor solid urease can contain alumina, silica, or a combination thereof.

In any embodiment of the first aspect of the invention, the urease pouchcan have a planar base with upwardly extending walls connecting to aplanar top wherein the walls are constructed from a rigid, fluidimpermeable material.

In any embodiment of the first aspect of the invention, the urease pouchcan have a base and top that are circular and wherein the upwardlyextending walls (a) extend parallel to the flow path, (b) slope inwardto an axis of the sorbent cartridge wherein the top has a smallersurface area than the base or (c) slope upwardly outward from the axisof the disc shape wherein the top has a larger surface area than thebase.

In one embodiment of the first aspect of the invention, the urease pouchcan be formed from a porous material, the porous material allowing fluidto pass through the urease pouch and substantially retaining the ureasein the urease pouch.

In any embodiment of the first aspect of the invention, the urease pouchcan have any one of (i) a top of the urease pouch having a pore sizesmall enough to prevent urease from passing through and a bottom portionof the urease pouch having a pore size to allow urease to pass through;(ii) a top of the urease pouch having a pore size to allow urease topass through and a bottom portion of the urease pouch having a pore sizesmall enough to prevent urease from passing through; or (iii) a top ofthe urease pouch having a pore size to allow urease to pass through anda bottom portion of the urease pouch having a pore size to allow ureaseto pass through.

In any embodiment of the first aspect of the invention, the urease pouchcan have a shape selected from the group consisting of a circular shape,a square shape, a triangular shape, a rectangular shape, a disc shape, acylindrical shape, a spherical shape, a substantially rectangular shape,or a cubical shape.

In any embodiment of the first aspect of the invention, the firstsection can further comprise at least one additional sorbent materialselected from the group consisting essentially of activated carbon,zirconium oxide, alumina, silica, and combinations thereof, and the oneor more sorbent materials in the second section can be selected from anyof zirconium phosphate, zirconium oxide, activated carbon, alumina,silica, and combinations thereof.

In any embodiment of the first aspect of the invention, the one or moresorbent materials in either the first or second section can berechargeable.

In any embodiment of the first aspect of the invention, the secondsection can be multi-use and the first section can be single use.

In any embodiment of the first aspect of the invention, the sorbentcartridge can have an inlet and an outlet for fluid connection to acontrolled compliant dialysis flow path.

In any embodiment of the first aspect of the invention, the sorbentcartridge can further comprise a urea sensor disposed in a fluid flowpath such that the urea sensor contacts fluid exiting the first sectionand can further comprise an alert that is triggered if the urea sensordetects urea in fluid exiting the first section.

In any embodiment of the first aspect of the invention, the sorbentcartridge can further comprise a valve disposed on the urease injectionport for controlling an introduction of a urease solution into the firstsection.

In any embodiment of the first aspect of the invention, the ureaseintroducer can be configured to receive an adjustable amount of ureaseor a fixed amount of urease.

Any of the features disclosed as being part of the first aspect of theinvention can be included in the first aspect of the invention, eitheralone or in combination.

The second aspect of the invention relates to a method that can comprisethe step of adding either solid urease or a urease solution to a sorbentcartridge adapted to replenish urease in the sorbent cartridge.

In any embodiment of the second aspect of the invention, the step ofadding the solid urease can comprise removing a urease pouch having areduced amount of urease, if present, and then adding a fresh ureasepouch into the sorbent cartridge.

In any embodiment of the second aspect of the invention, the step ofadding the urease solution can comprise injecting a urease solution intothe sorbent cartridge having a concentration between any of 1 mg/mL to250 mg/mL, 15 mg/mL to 150 mg/mL, 10 mg/mL to 100 mg/mL, or 75 mg/mL to250 mg/mL of urease into the sorbent cartridge.

In any embodiment of the second aspect of the invention, the ureasepouch or section can contain alumina, silica, or a combination thereof.

In any embodiment of the second aspect of the invention, the method cancomprise recharging an amount of one or more sorbent materials containedin the sorbent cartridge by passing a solution containing an appropriateamount of solutes for recharging the one or more rechargeable sorbentmaterials through the sorbent cartridge.

In any embodiment of the second aspect of the invention, the method cancomprise recharging an amount of one or more sorbent materials byreplacing one or more modules of a modular regeneration assemblycontaining an amount of one or more sorbent materials.

In any embodiment of the second aspect of the invention, a ureasebinding material such as alumina or silica substrate in the sorbentcartridge can be “recharged” once the sorbent cartridge is replenishedwith urease. Thereby, a single cartridge design with all non-watersoluble, rechargeable components can be provided to simplify design andreduce cost per session.

Any of the features disclosed as being part of the second aspect of theinvention can be included in the second aspect of the invention, eitheralone or in combination.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a sorbent cartridge having a urease pouch, a urease door,and a urease injection port.

FIG. 2 shows a sorbent cartridge having a urease pouch and a ureasetray.

FIG. 3 shows a urease pouch containing urease.

FIG. 4 shows an exemplary embodiment of a sorbent cartridge.

FIG. 5 is a top view of a disc-shaped urease pouch.

FIG. 6 is a front view of a rectangular-shaped urease pouch.

FIG. 7 is a perspective view of a rectangular urease pouch.

FIG. 8a is a side view of a string of disc-shaped urease pouches.

FIG. 8b is a top view of a string of disc-shaped urease pouches.

FIG. 8c is a side view of a string of disc shaped urease pouchesconnected by their edges.

FIG. 8d shows a top view of a string of disc shaped urease pouchesconnected by their edges.

FIG. 9a is a side view of a string of rectangular urease pouches.

FIG. 9b is a top view of a string of rectangular urease pouches.

FIG. 9c is a top view of a string of rectangular urease pouchesconnected by their edges.

FIG. 10 is a side view of a sorbent cartridge containing activatedcarbon, hydrous zirconium oxide, urease, alumina, and zirconiumphosphate.

FIG. 11a is a perspective view of a urease pouch having the ability toopen.

FIG. 11b is a perspective view of a urease pouch in an open state.

FIG. 12a is a perspective view of a rigid or semi-rigid urease pouchwith an interior seal member.

FIG. 12b a perspective view of a rigid urease pouch with an exteriorseal member.

FIG. 13 is a perspective view of a urease pouch with an internalseparator.

FIG. 14 is a perspective view of a urease pouch with an o-ring sealmember.

FIG. 15 is a perspective view of a urease pouch with an elastomericmaterial disposed on the side of the urease pouch.

FIG. 16 is a perspective view of a urease pouch and cartridge with a keyfunction to ensure correct alignment.

FIG. 17 is a perspective view of a urease pouch with a double layer offabric in the center to control flow through the urease pouch.

FIG. 18a is a perspective view of a urease pouch with a top and bottomsurface that is permeable to dissolved urease.

FIG. 18b is a perspective view of a urease pouch with a top surface thatis impermeable to dissolved urease and a bottom section that ispermeable to dissolved urease.

FIG. 18c is a perspective view of a urease pouch with top and bottomsurfaces that are impermeable to dissolved urease.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the relevant art.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “adapted to receive” refers to a component wherein introductionof a substance into the component is possible.

An “adhesive” is any substance known in the art for use in affixing onesurface to another surface, or to seal two surfaces together.

An “adjustable amount” refers to an amount of a material such as asorbent material that can be, but is not required to be changed during adialysis session.

An “ammonium sensor” is a sensor that is capable of detecting thepresence of, or concentration of, ammonium ions.

The term “appropriate amount of solutes” refers to an amount of one ormore solute(s) that is sufficient to accomplish a particular task. Forexample, an “appropriate amount of solutes” necessary to recharge thezirconium phosphate in a sorbent cartridge is the amount of sodium andhydrogen necessary to recharge the zirconium phosphate. The appropriateamount can be greater than the minimum amount necessary to accomplishthe particular task.

An “axis of the urease pouch” describes an imaginary line runningvertically through the center of the urease pouch, situated in thecenter of the surface of the urease pouch when viewed from the topperspective.

A “blood urea nitrogen assay” is any analytical test that can determinethe concentration of urea in blood or other fluids.

The term “cartridge” refers to any container designed to contain apowder, fluid, or gas made for ready connection to a device, structure,system, flow path or mechanism. The container can have one or morecompartments. Instead of compartments, the container can also becomprised of a system of two or more modules connected together to formthe cartridge wherein the two or more modules once formed can beconnected to a device, structure, system, flow path or mechanism.

A “chemical sensor” is a sensor that senses one or more variables basedon the chemical properties of a component of a medium.

A “circular shape” describes a urease pouch constructed in a generallyround shape having the form of a circle. This term is not intended tolimit the shape of the urease pouch to any particular size ordimensions, and may encompass oval or oblong configurations as well.

A “compartment” means a part or a space designated, defined, marked orpartitioned off from a structure. For example, a urease compartment in asorbent cartridge is space defined within the sorbent cartridgecontaining urease. Optionally, the compartment can be in selected fluidcommunication with other compartments or modules of the sorbent system.The compartment can be physically separated or marked off without aphysical barrier.

A “component” is any portion of a larger system. Non-limiting examplesof components are containers, reservoirs, sensors, modules, andsorbents.

The term “comprising” includes, but is not limited to, whatever followsthe word “comprising.” Thus, use of the term indicates that the listedelements are required or mandatory but that other elements are optionaland may or may not be present.

The term “consisting of” includes and is limited to whatever follows thephrase “consisting of” Thus, the phrase indicates that the limitedelements are required or mandatory and that no other elements may bepresent. The term “consisting essentially of” includes whatever followsthe term “consisting essentially of” and additional elements,structures, acts or features that do not affect the basic operation ofthe apparatus, structure or method described.

The term “container” as used herein is a receptacle that may be flexibleor inflexible for holding any fluid or solid, such as for example aspent dialysate fluid, or a sodium chloride or sodium bicarbonatesolution or solid, or urease, or urease/alumina, and the like.Generally, a container is a component of a larger system. A “sorbentcontainer” is any receptacle configured to hold one or more sorbentmaterials. Similarly, a “urease container” is any receptacle configuredto hold urease.

The term “contain” as used herein means to keep a material within aspecific place. “Contain” can refer to materials that are placed withina compartment, absorbed onto a component, bound to a component, or anyother method of keeping the material in a specific place.

“Dialysate” is the fluid that passes through the dialyzer on the side ofthe dialysis membrane that is opposite to the fluid (e.g. blood) that isbeing dialyzed.

“Dialysis” is a type of filtration, or a process of selective diffusionthrough a membrane. Dialysis removes solutes in the blood of a specificrange of molecular weights via diffusion through a membrane from a fluidto be dialyzed. During dialysis, a fluid to be dialyzed is passed on oneside of a filter membrane, while dialysate is passed on the other sideof that membrane. Dissolved solutes are transported across the filtermembrane by diffusion between the fluids. The dialysate is used toremove solutes from the blood being dialyzed. The dialysate can alsoprovide enrichment to the other fluid.

A “disc-like shape” describes a urease pouch forming a flat, circularshape, as in a compressed cylinder. This definition is not intended tolimit the dimensions or radius of the urease pouch, and may thereforeencompass discs having an oval shape, and discs of any radial width orthickness.

A “double layer of material”, “double layer of fabric” or “double layer”describes a second layer of material of the same or smaller area thanthe primary layer of material, disposed on the surface of the primarylayer of material forming a surface of a urease pouch. The material usedto form the double layer can be the same or different from the materialforming the primary layer. Any rigid or flexible porous material knownin the art is contemplated.

An “elastomer” or “elastomeric material” is a material comprising apolymer having high elasticity, such that the material may be easilystretched and shaped to be adapted to an internal cavity defined by asorbent cartridge.

“Engagement members” allow compartments to cooperatively engage. Incertain embodiments, these engagement members may be clasps or latches.In one embodiment, an engagement member allows for coupling of a topportion and a bottom portion of a urease pouch that can be opened andresealed.

An “exterior side” is a portion of a container or component that is onthe outside of the container or component, as opposed to an “interiorsection” of a container or component, which denotes the inside of thecontainer or component.

A “fixed amount” refers to an amount of sorbent material that cannot bechanged during a particular dialysis session. However, the “fixedamount” as used in the context of the sorbent cartridge of the presentinvention can change from one dialysis session to another dialysissession, or from one patient to another patient. For example, a firstdialysis session for a patient A at time X has a “fixed amount” ofrechargeable sorbent materials while a second dialysis session for thesame patient A at time Y can have a different “fixed amount” ofrechargeable sorbent materials from the “fixed amount” at time X.Similarly, patient A can have a different “fixed amount” of sorbentmaterials from a patient B.

A “flexible structure” describes a urease pouch being formed of a porousmaterial, wherein the urease pouch can be manipulated to fit an internalcavity defined by a sorbent cartridge.

“Flow” refers to the movement of a fluid or gas.

A “fluid” is a liquid substance optionally having a combination of gasand liquid phases in the fluid. Notably, a liquid, as used herein, cantherefore also have a mixture of gas and liquid phases of matter.

The term “fluid communication” or “fluid connection” refers to theability of fluid or gas to move from one component or compartment toanother within a system or the state of being connected, such that fluidor gas can move by pressure differences from one portion that isconnected to another portion.

A “fluid impermeable material” is any material through which fluidcannot pass.

The term “fluidly connectable” refers to the ability of providing forthe passage of fluid or gas from one point to another point. The twopoints can be within or between any one or more of compartments,modules, systems, components, and rechargers, all of any type.

“Functional capacity” is the ability of a material to accomplish thematerial's intended function. In some instances functional capacity canrefer to the ability of a sorbent material to remove specific solutesfrom a fluid, or to transform specific solutes into other materials.

“Hermetically sealed” refers to a seal that is airtight, orsubstantially impermeable to gases or fluids.

“Immobilized,” as used to refer to a chemical component, refers to aconfiguration wherein a chemical component is held in place by someforce. The force may be provided by absorption, adsorption, adhesion, orany other method for the chemical to be held in place.

The term “impregnated” describes any process known to a person ofordinary skill in the art by which a material may be caused to absorb orbe saturated with a substance. In one embodiment, the material forming aurease pouch may be impregnated with an anticoagulant, such that thesurface of the urease pouch absorbs the anticoagulant.

A “modular dialysate regeneration assembly” or “modular regenerationassembly” is one or more sorbent compartment containing at least onesorbent material attached to at least another sorbent compartment. Thesorbent compartment can be the same or different size and/or containdifferent or the same amount of sorbent material.

“Module” or “modular” refers to a discreet component of a system. Eachof the modules can be fitted to each other to form a system of two ormore modules. Once fitted together, the modules can be in fluidconnection and resist inadvertent disconnection. A single module canrepresent a cartridge to be fitted to a device or mechanism if themodule is designed to contain all the necessary components for anintended purpose such as a sorbent for use in dialysis. In such a case,the module can be comprised of one or more compartments within themodule. Alternatively, two or more modules can form a cartridge to befitted to a device or mechanism where each module individually carriesseparate components but only when connected together contain insummation all the necessary components for an intended purpose such as asorbent for use in dialysis. A module can be referred to as a “firstmodule,” “second module,” “third module,” etc. to refer to any number ofmodules. The designation of “first,” “second,” “third,” etc. does notrefer to the respective placement of the module in the direction offluid or gas flow, but merely serves to distinguish one module fromanother unless otherwise indicated.

“Multi-use” refers to a section of a sorbent cartridge that can berecharged, as used herein, such that after recharging, the sorbentcartridge can be placed back into service for dialysis. A multi-usesection of a sorbent cartridge requires recharging of the sorbentmaterials within the sorbent cartridge, but not necessarilyreplenishment of the sorbent materials.

An “optical sensor” is a sensor that senses one or more variables basedon changes in the light emitted from, reflected from, absorbed by, orthat travels through a medium.

The terms “pathway,” “conveyance pathway,” “fluid flow path,” and “flowpath” refer to the route through which a fluid or gas, such as dialysateor blood travels.

A “planar top” or “planar base” is a surface perpendicular to the axisof the urease pouch culminating at the uppermost portion of the upwardlyextending walls of a urease pouch, or a flat surface culminating at thebottommost portion of the downwardly extending walls of a urease pouch,respectively. The planar top may be any geometric shape and dimensionscomplementary to the upwardly extending walls of the urease pouch, forexample round, square, triangular or rectangular. A circular planar topor planar base is a flat surface having a circular shape, while arectangular planar top or planar base is a flat surface having a squareor rectangular shape.

The term “pore size” refers to the size of a small interstice or holeadmitting absorption or passage of liquid.

A “porous material” may describe any suitable porous material known inthe art from which a urease pouch may be constructed. For example, theporous material can include, but is not limited to, bolting cloth,cotton, ashless filter paper, Dacron and polyethylene terephthalate. Theporous material chosen for individual urease pouches may be selectedbased upon specific porosity in view of the sorbent material to becontained within the urease pouch.

“Recharging” refers to the process of treating a sorbent material torestore the functional capacity of the sorbent material, so as to putthe sorbent material back into a condition for reuse or for use in a newdialysis session. In some instances, the total mass, weight and/oramount of “rechargeable” sorbent materials remain the same. In otherembodiments, the total mass, weight and/or amount of “rechargeable”sorbent materials may change. Without being limited to any one theory ofinvention, the recharging process may involve exchanging ions bound tothe sorbent material with different ions, which in some instances mayincrease or decrease the total mass of the system. However, the totalamount of the sorbent material will in some instances be unchanged bythe recharging process. Upon a sorbent material undergoing “recharging,”the sorbent material can then be said to be “recharged.” Recharging ofrechargeable sorbent materials is not the same as replenishing of aparticular sorbent material such as urease. Notably, urease is notgenerally “recharged,” but can be is replenished, as defined herein.

“Replenishing” means to add back into a system, section or module, amaterial that was previously removed, reduced, depleted, or taken outfrom that system, section or module. For example, after introducing anamount of a sorbent material, e.g., urease, that was reduced in quantityand/or functional capacity in a compartment, the compartment with thefreshly introduced sorbent material can then be said to be“replenished.”

“Reusable” refers in one instance to a material that can be used morethan one time, possibly with treatment or recharging of the materialbetween uses. Reusable may also refer to a cartridge that contains amaterial that can be recharged by recharging the material(s) containedwithin the cartridge.

A “rigid structure” describes a urease pouch being formed of inflexiblematerial such that the urease pouch cannot be manipulated and reshapedto be adapted to an internal cavity defined by a sorbent cartridge, butinstead maintains its shape.

A “section” refers to any portion of a larger component. A section canbe referred to as a “first section,” “second section,” “third section,”etc. to refer to any number of sections. The designation of “first,”“second,” “third,” etc. does not refer to the respective placement ofthe section in the direction of fluid or gas flow, but merely serves todistinguish one section from another unless otherwise indicated.Additionally, each section can be optionally physically separated suchas by a divider or wall; however, referring to a particular section doesnot necessarily require physical separation and can merely refer to aparticular location in which a material is contained.

A “semi-rigid structure” describes a urease pouch having surfaces thatcan be flexed, but that are substantially rigid unless force is appliedto cause the surfaces to flex.

A “sensor” is a component capable of determining the states of one ormore variables in a system. In one embodiment, a sensor may be capableof sensing the presence and/or concentration of at least one compound inthe fluid flowing through at least one urease pouch, using any meansknown in the art.

A “separator” is a layer of flexible or rigid material positioned withina urease pouch that divides the urease pouch into top and bottomportions, such that sorbent materials housed in the top and bottomportions, respectively, do not come in contact with each other. Theseparator is formed of a porous material such that spent dialysate orother liquid may flow between the top and bottom portions of the ureasepouch through the separator, but such that the sorbent materials housedin the top and bottom portions of the urease pouch cannot pass throughthe separator.

A “sewn stitch” is a method of joining two surfaces together using athread composed of any material known in the art.

“Single-use” refers to a component, compartment, or module that is notcapable of being recharged as defined herein. Oftentimes, a single usecompartment can be replenished, as defined herein, with at least onematerial, e.g., urease, such that the compartment may be used in anotherdialysis session, but remains “single use” in the sense that thematerial is only being replenished, and not recharged. When the singleuse compartment is no longer suitable for use in dialysis, the singleuse compartment may be discarded whereas a “rechargeable” compartmentcan be recharged and put back into operation.

“Sorbent cartridge” refers to a cartridge that can contain one or moresorbent materials. The cartridge can be connected to a dialysis flowpath. The sorbent materials in the sorbent cartridge are used forremoving specific solutes from solution, such as urea. The sorbentcartridge can have a single compartmental design wherein all sorbentmaterials necessary for performing dialysis are contained within thesingle compartment. Alternatively, the sorbent cartridge can have amodular dialysate regeneration assembly wherein the sorbent materialsare dispersed across at least two different modules, which can beconnected to form a unitary body. Once the at least two modules areconnected together, the connected modules can be referred to as asorbent cartridge, which can be fitted to a device or mechanism. When asingle module contains all the sorbent materials necessary forperforming dialysis, the single module can be referred to as a sorbentcartridge.

“Sorbent materials” are materials capable of removing specific solutesfrom solution, such as urea or urea byproducts.

“Spent dialysate” is a dialysate contacted with blood through a dialysismembrane and contains one or more impurities, or waste species, or wastesubstances, such as urea.

“Solid urease” refers to urease in the solid phase of matter. The solidurease can be in a block of solid urease or in powdered form.

A “square” or “rectangular” shape describes a urease pouch having fouredges and four angles. This description is not intended to limit thesize and dimensions of the urease pouch, and may therefore encompassurease pouches having corners with angles greater than or less thanninety degrees, and with edges of differing lengths with respect to eachother.

The term “substantially retains” when referencing a urease pouch meansthat the urease pouch retains greater than 75% of the sorbent materialinside.

A “triangular shape” describes a urease pouch having three edges andthree corners, wherein the edges and corners may vary in length anddegree individually and with respect to each other.

“Upwardly extending walls” and “perpendicularly extending walls”describe the surfaces extending radially outward from the top and bottomsurfaces of a urease pouch. For example, in a urease pouch having adisc-like shape, the circular top and bottom portions of the ureasepouch are connected by the rounded upwardly extending wall of the ureasepouch. The upwardly extending walls may be of any shape or dimensionscomplementary to the corresponding top and bottom portions of the ureasepouch. In the case of a triangular shaped urease pouch, the upwardlyextending walls would extend from a bottom portion of the urease pouchand culminate at a vertex, in the absence of a top portion.

The term “urease compartment” or “urease container” refers to a definedspace or partition of any kind made from any material adapted forcontaining urease.

The term “urease door,” or “door,” refers to a portion of a componentsuch as a sorbent cartridge that can be opened, and the contents of thesorbent cartridge behind the door can optionally be replaced.

The term “urease injection port” refers to a temporary or non-temporaryopening or passageway allowing for the entry of urease from onecompartment to another.

A “urease introducer” is any component of a sorbent cartridge thatallows, facilitates, or provides for an amount of urease to be added toa sorbent cartridge. The use of the term introducer is used in thebroadest sense. For example, the urease introducer can be an inlet, aflow passageway, a tube, a tray that functions to introduce urease intoa defined compartment, or any other means that facilitates theintroduction of urease.

The term “urease pouch” refers to a structure that contains at leasturease and optionally one or more other sorbent material, and can beconstructed from a material that can allow fluid to freely pass throughthe urease pouch while keeping the sorbent material inside.

A “urea sensor” is a component capable of detecting the presence of, orconcentration of, urea in a fluid.

The term “urease solution” refers to any aqueous solution beingformulated by blending a solvent, such as water based solvent, andurease. The solution can have optional components such as bufferingcomponents.

The term “urease tray” refers to a drawer structure having a housing,generally being a sorbent cartridge, wherein the urease tray defines aninterior volume defined therein that can be adapted to receive, forexample, a urease pouch, module or loose sorbent material. The drawercan be “slideably movable,” or a “slideable tray” with respect to theinterior volume of the housing between a first closed position, whereinthe compartments are enclosed within the interior volume, and a secondopen position, wherein the compartments are at least partiallyaccessible. The “urease tray” can also optionally have a mechanism forcontrollably locking and/or sealing the drawer in the first closedposition.

A “valve” is a device capable of directing the flow of fluid or gas byopening, closing or obstructing one or more pathways to allow the fluidor gas to travel in a particular path. One or more valves configured toaccomplish a desired flow can be configured into a “valve assembly.”

Urease Introduction System

The first and second aspects of the invention allow a user to add anamount of urease, in solid or solution form, into a fluid flow pathusing a urease pouch containing urease. In any embodiment of the firstor second aspects of the invention, the urease solution can be injectedinto the fluid flow path and can travel through the fluid flow pathuntil the urease solution contacts the urease pouch. The urease can thenbe adsorbed by any known material known to bind urease such as alumina,silica, or combinations thereof, in the urease pouch, or contained bythe urease pouch without the use of the binding material where theurease will stay for the duration of dialysis. The urease can beimmobilized or bound by any known means or material known by those ofordinary skill such as electrostatic or enzymatic binding. The ureasecan further be bound by any intermolecular interaction such as van derWaals forces, or by adsorption. In any embodiment of the first or secondaspects of the invention, a urease pouch containing urease can be addedas necessary to the system. By adding fresh urease in this fashion,urease can be added to either open or closed sorbent systems. Further,the system can be used with a reusable sorbent cartridge. In otherwords, the sorbent cartridge can contain all non-water soluble,rechargeable components such as zirconium phosphate and alumina(excluding urease) inside the sorbent cartridge. Providing urease via aurease introducer wherein the urease travels into a urease pouch, oradding a fresh urease pouch to a sorbent cartridge, allows the sorbentcartridge to be shipped or stored without the urease or urease pouchpresent, while the urease or urease pouch can be added prior to use,during use, or after the sorbent cartridge is used. The adjustableaspect of urease introduction can reduce costs associated with thecomplexity and timing of manufacturing a sorbent cartridge containing aurease pouch. Notably, depending on such factors as the formulation andthe storage state of the urease, the urease may have a limited shelflife. By adding the urease or urease pouch just prior to startingdialysis, the sorbent cartridge can be stored for long periods of timewithout problems to the urease.

Moreover, the sorbent cartridge can be replenished with fresh urease foreach dialysis session wherein replenishing the urease in the sorbentcartridge can result in the recharging of alumina with urease in thesorbent cartridge for additional dialysis sessions. In particular, therecharging of sorbent materials, such as alumina or zirconium phosphate,describes the ability to restore or enhance the functional capacity ofthe material. For example, alumina or zirconium phosphate can berecharged and restored to functional capacity by passing a solutioncontaining the appropriate amount of solutes over the alumina orzirconium phosphate during a recharging process. Similarly, arechargeable section or module can be recharged by passing the necessarysolution through the section or module to restore the functionalcapacity of the module or section. In contrast, a replenishable sorbentmaterial, in which the functional capacity has been reduced, is requiredto be replenished as described herein.

In any embodiment of the first or second aspects of the invention, the“urease pouch” can contain urease, with or without zirconium phosphate.Zirconium phosphate is a rechargeable, expensive material as opposed tothe cheaper urease. The urease can be replenished as explained herein.Zirconium phosphate, which can be recharged, as defined herein, does notneed to be placed in the urease pouch, and can instead be positioneddirectly in a sorbent cartridge without the need for a urease pouch.Thereby, a single cartridge design can be provided to simplify designand reduce cost per session.

The urease in a urease pouch can be replenished as shown in FIG. 1. Asecond section of a sorbent cartridge can contain sorbent materials suchas zirconium phosphate or zirconium oxide. A first section of a sorbentcartridge 1 can contain a disc-shaped urease pouch 2, which in anyembodiment of the first or second aspects of the invention may containalumina, silica, or combinations thereof, and in any embodiment of thefirst or second aspects of the invention may not contain alumina, silicaor a combination thereof. The urease pouch 2 can be placed into thefirst section or a bottom portion of the sorbent cartridge 1. Fluid canenter the sorbent cartridge 1 through inlet 7 and exit through outlet 8.Urease can be injected into a urease injection port 3 through injectionsite 9, which can be placed in a fluid flow path before the urease pouch2, such as on the inlet 7. The urease injection port 3 can be in fluidcommunication with the inlet 7 of the sorbent cartridge 1. A bottom-sideof the urease pouch 2 can be constructed from a material that has alarge enough mesh size to allow the urease to enter the urease pouch 2.A top-side of the urease pouch 2 can be constructed from a material witha mesh size small enough so that the urease cannot move out of theurease pouch 2 as explained herein. In any embodiment of the first orsecond aspects of the invention, the urease pouch 2 can contain alumina,silica, or a combination thereof, which can immobilize the urease afterthe urease enters the urease pouch 2. In any embodiment of the first orsecond aspects of the invention, the urease pouch can be constructedfrom a material with a mesh size large enough so that urease can movefrom the urease pouch and immobilized on a sorbent material, such asalumina, downstream of the urease pouch. Before, during, or after adialysis session, or whenever the amount of urease in the first sectionof the sorbent cartridge 1 is reduced, the user can inject a freshamount of urease into the first section of the sorbent cartridge 1through injection port 3. The urease will travel from the injection port3 into the urease pouch 2, where the urease will be immobilized byeither the alumina, silica, or a combination thereof, within the ureasepouch 2, or by the top of the urease pouch 2, which has a mesh size thatis too small to allow urease to pass out of the urease pouch 2.

In any embodiment of the first or second aspects of the invention, theurease pouch can be present in the sorbent cartridge upstream of a layeror pouch containing activated carbon. This ensures that portions of theurease injected into the sorbent cartridge are not removed from solutionby the activated carbon prior to reaching the urease pouch, where theurease can be immobilized by alumina, silica or a combination thereofwithin the urease pouch, or because the top portion of the urease pouchhas a mesh size too small to allow the urease to pass out of the ureasepouch. In any embodiment of the first or second aspects of theinvention, the urease pouch can be downstream of the layer or pouchcontaining activated carbon. Urease can function in order to breakdownurea into ammonium and carbon dioxide, without the urease being bound tothe alumina or silica, or contained within a urease pouch. Importantly,because urease is water soluble, the urease should bind to somehydrophobic material within the cartridge, or be immobilized in a ureasepouch, so that the urease doesn't simply pass through the cartridge.Alumina or silica is generally used for this purpose, but anyhydrophobic, non-water-soluble material could work for this purpose. Insome cases, the urease can bind to the other sorbent materials withinthe cartridge, such as activated carbon, zirconium phosphate orzirconium oxide, without a reduction in urease activity. In anyembodiment of the first or second aspects of the invention, the othersorbent materials, such as activated carbon, zirconium oxide orzirconium phosphate, can bind urease that migrates from the alumina orsilica layer, or from the urease pouch, while the urease can remainactive. In embodiments of the first or second aspects of the inventionwherein the activated carbon layer is downstream of the alumina orsilica layer, or downstream of the urease pouch, the activated carboncan act as a safety backup, to capture urease that migrates through thealumina or silica, or the urease pouch, and would otherwise leave thesorbent cartridge. In any embodiment of the first or second aspects ofthe invention, a carbon loaded filter pad with a pore size large enoughto allow urease to pass through the filter can be placed upstream of thealumina or silica layer, or the urease pouch. The carbon loaded filterpad can help to distribute the fluid flow through the cartridge, andremove trace contaminants in the starting water that could degrade thefunctionality of the urease. In any embodiment of the first or secondaspects of the invention, the carbon loaded filter pad can have a poresize small enough to capture the urease.

The functional amount of the urease may be reduced in several ways: (1)the functional amount of urease may be reduced if the urease is strippedoff of the sorbent cartridge due to the recharging of other sorbentmaterials, (2) by leaching out during dialysis, or during maintenance ofthe sorbent cartridge, or (3) by modification or rearrangement of theurease structure to make the urease less active.

In any embodiment of the first or second aspects of the invention, thefirst section of the sorbent cartridge 1 can be adapted to receiveurease through a urease door 4. The urease door 4 can be disposed on anexterior side of the sorbent cartridge 1. The urease door 4 providesaccess to an interior of the sorbent cartridge 1. The urease pouch 2 ofFIG. 1 can be removed through urease door 4. The urease door 4 can beopened by pivoting the urease door 4 on hinge 5. A fresh urease pouch,either containing alumina, silica or a combination thereof, or with atop mesh size small enough to not allow urease to flow through, can beplaced into the sorbent module through urease door 4. In any embodimentof the first or second aspects of the invention, the urease pouch mayallow dissolved urease to flow out of the pouch where the dissolvedurease can be immobilized by alumina, silica, or a combination thereof,downstream of the urease pouch. A correct amount of urease can then beinjected into the injection port 3, as required before, after, or duringa dialysis session. The urease, once injected, can travel through afluid flow path via the inlet 7 and into the urease pouch 2. However, inany embodiment of the first or second aspects of the invention, theurease cannot migrate past the top-side of the urease pouch 2, and as aresult the urease should stay within the urease pouch 2. In anyembodiment of the first or second aspects of the invention, additionalalumina, silica, or a combination thereof, in layers appurtenant to theurease pouch 2 can be added to reduce urease migration, sequester ureasewithin the urease pouch 2 or immobilize the urease after flowing out ofurease pouch 2. In any embodiment of the first or second aspects of theinvention, urease pouches or modules containing other sorbent materialsmay be included in the sorbent cartridge 1. In any embodiment of thefirst or second aspects of the invention with a urease door 4, theinjection port 3 is not necessary. The user can simply insert a newurease pouch containing urease through the urease door 4, wherein thefresh urease pouch contains the necessary urease and so no injection isnecessary.

Urease door 4 can be sealed by any known method in order to preventleakage when closed and the sorbent cartridge 1 is in use. In anyembodiment of the first or second aspects of the invention, anelastomeric material, such as an o-ring, can be placed on the ureasedoor 4, the sorbent cartridge 1 or both in order to create a seal. Inany embodiment of the first or second aspects of the invention, gasketsor grease can be used in order to seal the urease door 4 to the sorbentcartridge 1.

In any embodiment of the first or second aspects of the invention, anoptional valve 10 can be placed downstream of the urease injection port3. The valve 10 can control fluid access from the urease injection port3 into the sorbent module 1. The valve 10 allows the system to controlthe amount of urease that can be injected into the sorbent cartridge,and also the timing of the urease injection.

In any embodiment of the first or second aspects of the invention,another layer containing alumina, silica or a combination thereof,without bound urease can also be positioned after the alumina or silicaand urease layer 2 to prevent urease migration.

The sorbent materials, other than urease, can be recharged by passing asolution containing the appropriate amount of solutes through thesorbent cartridge. The urease, although potentially removed during thisprocess, can then be replenished by introducing new urease through theurease injection port, or through adding a new urease pouch to thesorbent cartridge. This allows the urease within the sorbent cartridgeto be fully replenished without the need to remove or disassemble thesorbent cartridge in order to refill the cartridge and respectivemodules or components with new urease. In any embodiment of the first orsecond aspects of the invention, the sorbent cartridge can be a singlefixed, durable column that allows for recharging of all of the sorbentmaterials within the sorbent cartridge except for urease, and foraddition of urease into the column. In this way, the sorbent cartridgedoes not need to be replaced in order to replenish the urease andrecharge the alumina.

In any embodiment of the first or second aspects of the invention, thesecond section of the sorbent cartridge can be multi-use. That is,because in any embodiments of the first or second aspects of theinvention, the sorbent materials within the second section of thesorbent cartridge can be recharged, the second section can be usedmultiple times without the need to replenish any of the materials. Incontrast, the first section can be limited to single-use such that oncethe amount of urease within the first section has been reduced, theurease must be replenished.

Any method of injecting the urease solution into the urease injectionport 3 is contemplated by this invention. For example, a user may fill asyringe with urease solution and discharge the syringe into theinjection port 3. The urease injection port 3 may be covered by aseptum, which can be pierced by the syringe. The septum can be made ofre-sealable rubber, silicone, or any other suitable material. One ofordinary skill will appreciate that many types of injection ports can beused for the intended purpose of injecting urease solution. In anyembodiment of the first or second aspects of the invention, the ureasesolution can simply be transferred by any suitable means into the ureaseinjection port 3, and then pumped into the rest of the dialysis systemusing a system of pumps and actuators. In any such embodiments of thefirst or second aspects of the invention, the urease injection port 3may be covered with a removable cap that can be removed prior toaddition of the urease solution. In any embodiment of the first orsecond aspects of the invention, the dialysis machine can automaticallyinject the urease into the injection port 3. A urease solution can beprovided for within the dialysis machine. Whenever the amount of ureasewithin the sorbent cartridge is reduced, the machine can automaticallyinject fresh urease into the urease injection port 3. In any embodimentof the first or second aspects of the invention, the dialysis machinecan meter in the correct amount of urease that is to be injected intothe urease injection port 3.

In any embodiment of the first or second aspects of the inventionutilizing a urease injection port, the urease injected can be a solutionof urease. The invention is adaptable to a wide range of fluids. Thefluid of the solution can be water, buffer, priming solution, or anyother fluid capable of dissolving the urease.

In any embodiment of the first or second aspects of the invention, thesorbent module 1 can be part of a modular dialysate regenerationassembly. That is, other modules containing sorbent materials can beattached to each other. In any embodiment of the first or second aspectsof the invention, the recharging of the sorbent materials in the moduleor modules that do not contain urease can be accomplished by simplyreplacing those modules. Dialysate regeneration refers to the process oftreating spent dialysate, containing solutes removed from the patient'sblood, with one or more sorbent materials in order to remove specificsolutes, such as urea, and thereby generate dialysate that can be reusedfor dialysis.

In any embodiment of the first or second aspects of the invention, anoptional urea detector 6 can be placed in the fluid flow path at somepoint after the urease layer of the sorbent module. A urea detector 6can detect urea that has not been converted to ammonia and CO₂ byurease. Urea can indicate insufficient urease being present in thesorbent cartridges of the present invention and that more urease may berequired to meet therapy goals. Moreover, urea can signal a need to addmore urease into the sorbent cartridge, or urea may signal that theprior urease addition did not work properly. In any embodiment of thefirst or second aspects of the invention, the system may give the useran audio or visual alert if the urea detector detects urea in the spentdialysate after passing through the urease containing module. Withoutbeing limited to any particular method, there are two general methodsfor the measurement of urea nitrogen. The diacetyl, or Fearon, reactiondevelops a yellow chromogen with urea quantified by photometry. Thereaction can be modified for use in autoanalyzers and can providerelatively accurate results. Enzymatic methods rely on an enzyme, whichcan convert urea to ammonia and carbonic acid. These products, which areproportional to the concentration of urea in the sample, can be assayedin a variety of systems, some of which are automated. One system checksthe decrease in absorbance at 340 mm when the ammonia reacts withalpha-ketoglutaric acid. Other systems can measure the rate of increasein conductivity of the solution in which urea is hydrolyzed.Alternatively, urea can be measured indirectly by an ammonia detectorlocated downstream of the urease layer and upstream of the zirconiumphosphate layer. In general, low or no detected ammonia in fluid afterpassing through the urease layer but before reaching the zirconiumphosphate layer can trigger an alert or workflow for adding fresh ureaseto a dialysis system. Any method of detecting the amount of urea that isconverted to ammonia in the sorbent cartridge is contemplated by theinvention. In addition to the methods above, the detection can beaccomplished by any means known in the art, including but not limitedto, the use of an optical sensor, a chemical sensor, a blood ureanitrogen assay, an ammonium sensor, or any combination thereof.

In any embodiment of the first or second aspects of the invention, anamount of urea converted to ammonia by the urease in a sorbent cartridgecan be detected, such as by detecting the amount of ammonia or urea inthe dialysate before and after passage of fluid through the sorbentcartridge. For example, a first fluid stream sample can be measured justprior to a sorbent cartridge, and a second fluid steam sample measuredjust after the sorbent cartridge. Any number of measurements can betaken such as an amount of ammonia present pre- and post-sorbent. Inparticular, if ammonia measurements indicate to one of skilled in theart that the zirconium phosphate has reached capacity, an alert can betriggered or a workflow initiated for introducing zirconium phosphatevia any of the described methods and features described herein. One ofordinary skill will understand that detection of ammonia may not be anindication of the sufficiency or insuffiency of urea conversion. Rather,detection of ammonium post-sorbent can indicate that the zirconiumphosphate has reached functional capacity. For example, low ammonialevels in the fluid post-sorbent cartridge can indicate that zirconiumphosphate has reached functional capacity in the sorbent cartridge.

In any embodiment of the first or second aspects of the invention, aurea detector can detect ammonia in the system that can indicate thatzirconium phosphate contained within the system has reached capacity. Inany embodiment of the first or second aspects of the invention, theamount of ammonia produced can be a function of the zirconium phosphatecapacity and the system can determine if zirconium phosphate is requiredby the system.

In any embodiment of the first or second aspects of the invention, thesorbent cartridges of the present invention can be adapted to receive anamount of urease that can be adjusted based on dialysis parameters. Anyamount of urease may be injected or added as described herein in orderto replenish the urease in the sorbent cartridge. Moreover, thereplenishing step can be performed before, after, or during dialysis, orduring priming of the system. If an amount or level of urease in thesorbent cartridge or dialysis system becomes insufficient or lower thanrequired levels during a dialysis session, the present invention canreplenish urease levels without halting the dialysis session.Critically, the adjustability of the amount of urease to be addedin-session can provide flexibility in type of treatment delivered andtherapy goals. The adjustable amount of urease can further provide forpersonalization of treatment and also result in a system that can beeasily adapted to provide treatment for different patients.Adjustability in urease can reduce waste and tailor treatment tospecific goals not possible with systems having not mechanism foradjusting an amount of urease being used during dialysis or acrossdifferent treatment sessions.

An amount of urease required may be reduced by introducing the ureaseonly when urease introduction is needed such as after priming of thesystem in preparation for use. One of ordinary skill can provide aspecific amount of urease needed for a particular patient viaprescription thereby customizing the amount of urease required to thespecific patient. The amount of urease added can be based on the patient(size, weight, BUN, etc.). Such patient customization or prescriptionscan be performed in lieu of a sensor-based system or in conjunction withsuch sensor-based systems. In particular, the sensor-based systemshaving sensors capable of providing feedback regarding an amount ofurease contained in the system and provides an input to further adjustthe amount of urease required. Urease can be added to the sorbentcartridge at any point, including before, during, or after a dialysissession.

In any embodiment of the first or second aspects of the invention, asshown in FIG. 2, a urease tray 15 can be included wherein the ureasetray 15 is slideably removable from the sorbent module 11, or hingeablydisposed on the sorbent module 11 by hinge 14. The urease tray 15 can beadapted to receive a urease pouch or solid urease as described herein.One skilled in the art will understand that any means of connectionbetween the sorbent module 11 and urease tray 15 is within the scope ofthis invention, and that in any embodiment of the first or secondaspects of the invention, hinge 14 is unnecessary. The urease tray 15can have a length, width, and height to define an interior region forreceiving solid urease or pouch of urease 16. In any embodiment of thefirst or second aspects of the invention, the urease tray 15 can behermetically sealed to prevent contamination or leaking when closed. Ahermetic seal can be created with the use of PTFE sealing rings,o-rings, grease or any other material known in the art capable ofcreating a hermetic seal disposed on the edges of urease tray 15.

The urease pouch or module is described herein. Fluid can enter thesorbent module 11 through inlet connector 18 and exit through outletconnector 19. The urease tray 15, in use, can fit into space 12 in thesorbent cartridge 11. The user can, whenever the amount of ureasepresent in the sorbent module 11 has been reduced, place a new ureasepouch or solid urease in the urease tray 16, and slide the urease trayinto space 12. Optional urea detector 17 can detect urea in the fluidleaving the urease/alumina pouch 16. In any embodiment of the first andsecond aspects of the invention, alumina can be placed after the space12 for the urease pouch 16 such as at the top of the space 13 in orderto bind the introduced urease, or to prevent urease migration beyond theintended location.

A porous urease pouch can be used as the urease source in a sorbentcartridge, as shown in FIG. 3. The urease pouch 21 can be made asdescribed herein, so that the alumina and urease 22 inside the ureasepouch 21 cannot move through the urease pouch 21 and out of the sorbentmodule, but so that the spent dialysate can move freely through theurease pouch 21 to contact the urease inside. In any embodiment of thefirst or second aspects of the invention, the material can be selectedwith a mesh or pore size small enough to allow small molecules to passthrough, but not allow free urease to pass through. Because in suchembodiments the urease is kept within the urease pouch, the urease mayreact with the urea in the spent dialysate while the urease is insolution, which may eliminate the need for alumina to support theurease. In any embodiment of the first or second aspects of theinvention, the pore size may be large enough to allow dissolved ureaseto flow through the pouch, where the urease can be immobilized byalumina within the sorbent cartridge downstream of the urease pouch. Inany embodiment of the first or second aspects of the invention, jackbean urease can be used or other forms of urease, both naturallyisolated or recombinant forms, known to those of ordinary skill. In anyembodiment of the first or second aspects of the invention, the ureasepouch can contain solid urease that can be dissolved by fluid thatenters the urease pouch.

The urease pouch 21 in FIG. 3 is shown as a disk-shaped pouch. However,any of the described embodiments of the first or second aspects of theinvention can be made in any shape, including a circular shape, a squareshape, a triangular shape, a rectangular shape, a disc shape, acylindrical shape, a spherical shape, a substantially rectangular shape,or a cubical shape. Each shape described can be substantially in theform described and can vary in dimensions without departing from thefirst or second aspects of the invention. For example, a pouch having agenerally spherical shape, which is slightly ovoidal, is contemplated bythe invention. Similarly, a disc having a tapered end on one or moreends to form a cone or being conoidal in form is also contemplated. Suchvariations from the generally described geometrical shapes are eachencompassed by the invention. In any embodiment of the first or secondaspects of the invention, the upwardly extending walls of the ureasepouch 21 can slope inward toward axis 23, creating a urease pouch with atop surface having a smaller surface area than the bottom surface. Inany embodiment of the first or second aspects of the invention, theupwardly extending walls can slope away from axis 23, creating a ureasepouch with a top surface having a larger surface area than the bottomsurface. In any embodiment of the first or second aspects of theinvention, the upwardly extending walls can be parallel to axis 23,creating a urease pouch with a top and bottom surface area that areequal. In any embodiment of the first or second aspects of theinvention, the size and shape of urease pouch 21 can be selected basedon the size and shape of the interior portion of the sorbent cartridge,in order to provide a seal between the sorbent cartridge and the ureasepouch 21 as described herein.

In any embodiment of the first or second aspects of the invention, theurease pouch may be constructed with a different pore size on the top ofthe pouch than on the bottom. For instance, the top of the urease pouchmay be constructed with a pore size that will substantially retain theurease within the urease pouch. The bottom of the urease pouch can beconstructed with a pore size that will allow dissolved urease to travelthrough the bottom of the urease pouch. In such embodiments of the firstor second aspects of the invention, urease in solution can enter theurease pouch through the bottom of the urease pouch, but cannot exit theurease pouch through the top of the urease pouch.

Any useable concentration of urease within the urease solution to beadded is within the scope of this invention. In any embodiment of thefirst or second aspects of the invention, the urease concentration canbe between 10 mg/mL and 100 mg/mL. In any embodiment of the first orsecond aspects of the invention, the urease concentration can be betweenany of 1 mg/mL to 250 mg/mL, 15 mg/mL to 150 mg/mL, 10 mg/mL to 100mg/mL, or 75 mg/mL to 250 mg/mL. One of ordinary skill can determine arange suitable for a particular patient or clinical outcome.

In any embodiment of the first or second aspects of the invention, theurease solution can be provided in a pre-packaged amount. Before adialysis session, whenever the amount of urease within the urease moduleor pouch is reduced, or after recharging the other sorbent materials,the pre-packaged amount of urease can be added to the sorbent cartridgeto ensure a fresh supply of urease within the sorbent cartridge. Thepre-packaged amounts can be between 1.3 mL and 13.3 mL of ureasesolution with an activity of 300 unit/mg. In any embodiment of the firstor second aspects of the invention, the pre-packaged amounts can bebetween any of 1.5 mL to 3.5 mL, 2.3 mL to 10.3 mL, or 5.0 mL to 12.3 mLor more. Indeed, the pre-packaged amounts can be in any suitable rangeof volumes or specific volume without limitation. In this manner, anamount of urease solution specific to a patient or desired clinicaloutcome can be added to a dialysis system prior to initiating a dialysissession or if urease levels are insufficient. In any embodiment of thefirst or second aspects of the invention, urease can be provided in aseparate sorbent module or container having a proper amount of urease tobe added. The separate sorbent module or container can ensure that thecorrect amount of urease is added to the sorbent cartridge convenientlyand easily, thereby limiting the number of opportunities for user errorand waste of sorbent materials. The separate sorbent module or containercan be single or multi-use depending on the design and type of sorbentmaterials contained herein. For example, a sorbent module containingzirconium phosphate packaged together with a urease/alumina layer can beused multiple times, whereas a module only containing alumina and ureasemay only be designed for single-use. Based upon the patient or desiredclinical outcome, the amount of urease can depend on the blood ureanitrogen (BUN) content of the patient's blood. For example, more ureasecan be added for patients with a higher BUN than for patients with alower BUN. Moreover, overweight patients may need more urease thanunderweight patients.

If an amount of the urease within the sorbent cartridges of the presentinvention has been reduced, or prior to using a sorbent cartridgeshipped without urease, a user can introduce the urease pouches and/orconcurrently inject urease solution via the urease injection port, orreplenish the urease pouch. In any embodiment of the first or secondaspects of the invention, the system can prompt the user to introduceone or more fresh urease pouch(es) or a set of modular pouches perspecified patient or therapy requirements into the sorbent cartridgebefore each dialysis session. The user prompts can also be generatedafter a set number of dialysis sessions, or whenever the amount ofurease within the sorbent cartridge is insufficient. In any embodimentof the first or second aspects of the invention, the urease solutioninjected into the urease injection port can be of a higherconcentration, and can be complimentary to the urease pouch. Theinjected urease solution can then be diluted by water as the solutionflows in a fluid flow path into the sorbent cartridge. In any embodimentof the first or second aspects of the invention, the user need onlyremove the used urease pouch containing urease and insert the new ureasepouch containing urease into the sorbent cartridge.

In order to test the effectiveness of urease solution injection forloading urease into a sorbent cartridge, such as with the ureaseinjection port described herein, as opposed to loading urease to acolumn as a dry powder, several experiments were run. These experimentsare described herein as Examples 1-4. Example 1 refers to the loading ofurease onto a column using a dry powder loading procedure. Examples 2and 3 are the analysis of the urease migration and urea conversionobtained from the dry powder loading procedure of Example 1. Example 4relates to the loading and analysis of urease onto a column using aurease solution.

Example 1

An Ace Glass 25 millimeter Adjusta-Chrom Jacketed Column (P/N 5819) waspacked with a mixture of 3.001 grams activated alumina (Shandong LuyeCo, Lot 20140811-1) and 0.0040 grams of purified urease (Tokyo ChemicalIndustry, Lot P7DWG-TJ). An additional 9.0070 grams of activated alumina(Shandong Luye Co, Lot 20140811-1) was added to the column and theoutlet frit and plunger were adjusted so that no dead space existedabove the alumina layer and locked into place. Heated water wascirculated through the external jacket of the column to maintain atemperature of 37° C. throughout the experiment. The column was primedby pumping base buffer (115 mMol sodium chloride and 25 mMol sodiumbicarbonate) at 15 ml/minute until the liquid level reached the top ofthe alumina then held for five minute without flow to allow the ureaseto distribute and bind to the alumina. After the hold period the primingsolution flow was restarted at 15 ml/min for an additional 5 minutes tocomplete the priming sequence. When the priming sequence was completedthe column feed was changed to a test solution containing 25 mMol/Literof urea (Sigma Aldrich) in base buffer. The flow rate was maintained at15 mL/min for 60 minutes. The column effluent was collected for ureasemigration analysis and separate 8 mL samples were collected after 10, 30and 60 minutes of test solution flow for urease conversion testing.

Example 2

A urea challenge solution was made containing 400 mMol/Liter phosphatebuffer and 400 mMol/L urea. A 1.8 mL sample from the pooled columneffluent from Example 1 was mixed with 1.8 mL of the urea challengesolution and incubated at room temperature for 10 minutes. Ammoniumlevels in the solution were measured using a Nova BioProfile 300analyzer every 10 minutes over a period of 50 minutes. The ammoniumconcentration was plotted as a function of time and a linear regressionwas performed to determine the urease activity of the solution. Theurease activity was then multiplied by the total volume of effluent runthrough the column to determine the total urease units (IU) thatmigrated during the test. For Example 1 the result was 53 InternationalUnits of migrated urease.

Example 3

The test samples collected at 10, 30 and 60 minutes in Example one wereused for this analysis. A 0.8 mL aliquot of test sample was mixed with a0.8 mL aliquot of 400 mM/L phosphate buffer and mixed vigorously. Theammonium concentration was determined using the Nova BioProfile 300analyzer using the automated machine procedure. The results werecompared to a standard curve measure in the same way using standard ofknown concentration. The ammonium concentration in the test sample isused to calculate the percent urea conversion for the urease/aluminareactor. For Example 1 the result was 53.4% urea conversion.

Example 4

The test system of Example 1 was modified to include a three way valvein the inlet feed line. The three way valve had one port compatible witha luer lock syringe and the other ports connected to the test solutionand test column inlet. The Ace Glass 25 millimeter Adjusta-ChromJacketed Column was packed with 12.001 grams of alumina (Shandong LuyeCo, Lot 20140811-1). A solution of 0.0079 grams urease (Tokyo ChemicalIndustry, Lot P7DWG-TJ) was mixed in 8.0 mL of base buffer (115 mMolsodium chloride and 25 mMol sodium bicarbonate) to make a solution ofapproximately 300 IU/mL. The urease was charged into the reactor byinjecting 1.3 mL of base buffer, followed by 4.0 mL of urease solutionand 1.8 mL of base buffer. The base buffer was used to fill the inletline before introducing the urease and to ensure all the urease wasflushed out of the inlet feed line and into the alumina. Afterintroduction of the urease, the column was tested according to themethod described in Examples 2-3. The urease migration for this testcolumn was 47 International Units and the urea conversion was 67.4%.

The results of the experiments in Examples 1-4 are summarized inTable 1. As can be seen in Table 1, the results obtained from the ureasesolution loading were comparable to the results obtained with dry powderloading. Although additional experiments will be necessary to determinethe superiority of one method over the other, the results demonstratethat a liquid load is possible without all of the enzyme migrating outof the column.

TABLE 1 Urease Urea Method of Urease Loading Migration Conversion DryPowder Loading (Example 1) 53 IU 53.4% Urease Solution Loading (Example4) 47 IU 67.4%

Sorbent Dialysis

One non-limiting exemplary sorbent cartridge is shown in FIG. 4. Spentdialysate or fluid can flow from the bottom of the sorbent cartridge 31to the top of the cartridge. The first sorbent material the spentdialysate or fluid contacts can be activated carbon 32. Activated carbon32 will remove nonionic toxins from the fluid by adsorption. Creatinine,glucose, uric acid, β2-microglobulin and other non-ionic toxins, excepturea, can be adsorbed onto the activated carbon, removing those toxinsfrom the fluid. Other non-ionic toxins will also be removed by theactivated carbon. The dialysate or fluid then continues through thesorbent cartridge 31 to the alumina and urease layer 33. The fluid canthen move through the sorbent cartridge 31 into the hydrous zirconiumoxide layer 34. The hydrous zirconium oxide layer 34 can removephosphate and fluoride anions, exchanging them for acetate anions.Alternatively, the layers 33 and 34 can be reversed wherein dialysateflows through the sorbent cartridge 31 first to the hydrous zirconiumoxide layer now positioned at 33, and then continue to move through thesorbent cartridge 31 into the alumina and urease layer now positioned at34.

Urease can catalyze the reaction of urea to form ammonia and carbondioxide. The result of this reaction is the formation of ammoniumcarbonate. The phosphate anions present in the fluid can also beexchanged for hydroxide ions on the alumina. As the fluid continuesthrough the sorbent cartridge 31 in FIG. 4, the fluid reaches anoptional alumina layer 35. The optional alumina layer 35 can remove anyremaining phosphate ions from the fluid and help retain urease withinthe sorbent cartridge 31, and in certain configurations this layer 35can exchange urea for ammonium and other components. The last layerthrough which the fluid travels can be the zirconium phosphate layer 36.In the zirconium phosphate layer 36, ammonium, calcium, potassium andmagnesium cations can be exchanged for sodium and hydrogen cations.Ammonium, calcium, potassium and magnesium ions all preferentially bindto the zirconium phosphate, releasing the hydrogen and sodium ionsoriginally present in the zirconium phosphate layer 36. The ratio ofsodium to hydrogen ions released depends on the ratio originally presentin the zirconium phosphate layer 36, and is therefore controllable. Theresult of the fluid passing through the sorbent cartridge 31 is that thefluid can be regenerated and form clean dialysate that can be safelypassed back through a dialyzer to a patient. In any embodiment of thefirst or second aspects of the invention, potassium, calcium, andmagnesium can be added to the clean dialysate to replace any ions whichwere removed by the sorbent cartridge. The ions can be added and orcontrolled via an infusate system that can be positioned on a section ofthe fluid flow path after the sorbent cartridge.

In any embodiment of the first or second aspects of the invention, thelayers, 32, 33, 34, and 35 can comprise a second section of a sorbentcartridge that can be detached from a first section of the sorbentcartridge comprising layer 36 containing zirconium phosphate. Thedetached or detachable section(s) can be separated from a system,module, cartridge or any component of the sorbent cartridges of thepresent invention. The detachable components can be connected by anysuitable means wherein the section can be taken out of a larger systemwith minimal time or effort. The detached component, section, or modulecan be optionally reattached to the system, module, cartridge or othercomponent.

In any embodiment of the first or second aspects of the invention, thesorbent materials, other than alumina, can be recharged by passing afluid containing the correct solutes through the material. For example,zirconium phosphate can be recharged by passing a fluid containinghydrogen and sodium ions through the zirconium phosphate. The hydrogenand sodium ions will replace the ammonium, potassium, calcium, magnesiumor other ions removed by the zirconium phosphate during dialysis, andthereby place the zirconium phosphate back in condition to be used insorbent dialysis. Zirconium oxide can be recharged by passing a solutioncontaining acetate ions through the zirconium oxide. The activatedcarbon can be recharged by passing heated water through the activatedcarbon. The amount of each of the solutions that must be passed throughthe respective sorbent materials depends on the amount of sorbentmaterial used. This process may strip the urease from the alumina,necessitating replenishment of the urease. In any embodiment of thefirst or second aspects of the invention utilizing alumina or silica asdescribed herein, the step of replenishing the urease in the system canresult in recharging of the alumina or silica.

Urease Pouches

The first and second aspects of the invention can utilize separateurease pouches that contain urease. Optionally, the urease pouches cancontain individual layers of other sorbent material, or multiple layersof sorbent material. Spent dialysate or water may pass through theurease pouch and into the urease or other optional sorbent materialswithin. The first and second aspects of the invention can utilizeseparate urease pouches that contain individual portions of sorbentmaterial, or multiple layers of sorbent material. The urease pouches canbe formed from a porous material wherein the urease pouches contain atleast one sorbent material. The porous material can allow fluid to passthrough the urease pouches but substantially retains the urease in theurease pouch. In any embodiment of the first or second aspects of theinvention, the porous material can allow fluid to pass through theurease pouches but can retain at least 98% by weight of urease in theurease pouch. In any embodiment of the first or second aspects of theinvention, the porous material can allow fluid to pass through theurease pouches but can retain anywhere from at least 70%, 75%, 80%, 85%,90%, 92%, 93%, 94%, 95%, 96%, or 97% by weight of urease in the ureasepouch.

The urease pouches can be constructed in any shape. For convenience,they are often drawn as circular or disc shaped. However, any of thedescribed embodiments of the invention can be made in any shape,including a circular shape, a square shape, a triangular shape, arectangular shape, a disc shape, a cylindrical shape, a spherical shape,a substantially rectangular shape, a cubical shape, etc. In anyembodiment of the first or second aspects of the invention, the shape ofthe urease pouch can be selected based on the shape of the interior ofthe sorbent cartridge.

For example, FIG. 5 depicts a disc-shaped urease pouch 41 containingsorbent material 42, whereas FIG. 6 shows a rectangular-shaped ureasepouch 51 containing sorbent material 52, and FIG. 7 shows a rectangularurease pouch 61. The urease pouches may be constructed of any knownmaterial, including filter paper, cloth, nylon, porous polymer and metalas described herein, and each may be constructed in any shape. In anyembodiment of the first or second aspects of the invention, the ureasepouch can contain a mixture of urease and alumina.

In any embodiment of the first or second aspects of the invention, theurease pouches can be configured as shown in FIG. 5. The urease pouch 41can be constructed of a material that can allow fluid to pass throughthe urease pouch 41, but will not allow urease 42 contained within theurease pouch 41 to pass out of the urease pouch 41. The urease can beplaced loosely in the urease pouch, allowing the urease to move withinthe urease pouch, but not to travel out of the urease pouch. The ureasepouch can be made in any size or shape. In any embodiment of the firstor second aspects of the invention, as shown in FIG. 6, the urease pouch51 can be roughly rectangular shaped. In any embodiment of the first orsecond aspects of the invention, as shown in FIG. 5, the urease pouch 41can be disc-shaped. In any embodiment of the first or second aspects ofthe invention, the urease pouch can be shaped to be adapted into aninternal cavity defined by a sorbent cartridge. In this way, the ureasepouch may fit in the space, such that there may be void space, but suchthat the urease pouch generally fits the space. For example, a sorbentcartridge having a cylindrical internal cavity can accommodate acircular or disc-shaped urease pouch, while a sorbent cartridge having aconical internal cavity could accommodate a triangular urease pouch, anda sorbent cartridge having a square or rectangular internal cavity couldaccommodate a square or rectangular-shaped urease pouch.

FIG. 7 shows a rectangular urease pouch embodiment in which the ureaseis contained in a raised inner portion of the urease pouch 61, while theouter perimeter of the urease pouch 61 having a finished or serratededge 62 is sealed by any means known in the art, including heat orpressure stamping, sewing, or adhesive sealing. The finished or serratededge 62 of the urease pouch 61 may be permanently sealed, or mayalternatively be resealable, such that the urease pouch 61 may be openedand reclosed. For example, the finished or serrated edge 62 may besealed with a resealable adhesive, hook and loop fasteners (not shown),or with interlocking ridges (not shown) that may be separated andreclosed by the user. Optionally, a latch member (not shown) may beincluded on the finished or serrated edge 62 of the urease pouch 61 toprovide additional strength in sealing the urease pouch 61. In anyembodiment of the first or second aspects of the invention, the outeredge may simply be a folded edge. In use, compression from the othermaterials within a sorbent cartridge can keep the folded edge sealed andthe sorbent materials inside the urease pouch 61. Alternatively, theurease pouch 61 may be sealed with drawstrings that when tightenedcreate a seal. In any embodiment of the first or second aspects of theinvention, the edges of the urease pouch 61 need not be serrated. Anymethod of creating a sealed urease pouch is contemplated by thisinvention. The edges of the urease pouches can be simply woven together,sealed by adhesive, or closed by any other fashion known in the art.

The size of the urease pouches used in the invention is flexible.Because different amounts of each sorbent material may be required for adialysis session, the urease pouches of the present invention may be inmultiple sizes. In any urease pouch, glass beads can be incorporatedinto the sorbent material to facilitate flow.

The urease pouches may be constructed of a flexible structure, a rigidstructure, or a semi-rigid material. In any embodiment of the first orsecond aspects of the invention, the urease pouches may be constructedout of both a flexible and a rigid material. For example, the top andbottom of the urease pouch may be constructed from a flexible material,while the sides of the urease pouch may be constructed from a rigidmaterial. In any embodiment of the first or second aspects of theinvention, the sides of the urease pouches can be fluid impermeable,while the top and bottom of the sorbent pouch can be permeable to fluid.In any embodiment of the first or second aspects of the invention, theurease pouches can be made out of a material such as a porous polymer.The polymer may be made porous by creating small holes or pores in anotherwise solid polymer material. In embodiments of the first or secondaspects of the invention where the urease pouch is made of fabric, theweave of the fabric can have a specified porosity suitable for use thesorbent material described herein for the intended use of dialysis. Thepolymer may be constructed from polyethylene terephthalate, high densitypolyethylene, low density polyethylene, polyvinyl chloride,polypropylene, polystyrene, or any other polymer known in the art. Thepores of the urease pouch material must be large enough to allow thespent dialysate to freely travel into and out of the urease pouch; whileat the same time must be small enough to keep the particles of theurease inside the urease pouch to minimize urease migration. For thisreason, urease pouches with different pore or mesh sizes can be utilizedfor different material layers. In any embodiment of the first or secondaspects of the invention, the urease pouch may be made out of a naturalfiber, such as cotton. In any embodiment of the first or second aspectsof the invention, the urease pouch may be constructed from ashlessfilter paper. The urease pouches may also be constructed out of asynthetic material such as Dacron, or polyethylene terephthalate.

In any embodiment of the first or second aspects of the invention,multiple urease pouches may be connected as a string of urease pouches,as shown in FIGS. 8a, 8b, 8c, 8d, 9a, 9b and 9c . For example, as shownin FIG. 8a and FIG. 8c , the individual urease pouches 71-75 may bepermanently or separably connected at their outer edges 76-80 in thecase of the disc shaped urease pouches of FIG. 8c and the outer edges86-90 of urease pouches 81-85 in the case of rectangular urease pouchesof FIG. 9c , by any means known in the art, including by perforations inthe material forming the outer edges 76-80 and 86-90. The materials ofwhich the individual urease pouches are composed may be selected withparticularity to urease. For example, urease has a molecular weight ofbetween 480 kDa and 545 kDa. As such, the urease pouch can beconstructed from a material that will not allow molecules with amolecular weight of between 480 kDa and 545 kDa to pass through. Anycombination of urease pouch materials and mesh sizes among the string ofurease pouches, and any number of individual urease pouches making upthe string of urease pouches, is envisioned. Additionally, the interiorportion of the urease pouches may be constructed in any shape, includingbut not limited to, rectangular or circular.

One non-limiting embodiment of the urease pouches of the first andsecond aspects of the invention is shown in FIG. 10. The sorbentcartridge 91 can comprise multiple sorbent pouches, including a sorbentpouch containing activated carbon 92, a sorbent pouch containing hydrouszirconium oxide 93, a sorbent pouch containing alumina and urease 94,and a secondary sorbent pouch containing alumina 95. In any embodimentof the first or second aspects of the invention, alumina can becontained in one sorbent pouch and the urease in another sorbent pouch.Spent dialysate can enter through the bottom surface 97 of the sorbentcartridge 91, and flow through each of the sorbent pouches sequentially,and then flow out of the sorbent cartridge 91 through the top surface 96of the sorbent cartridge 91. In this way, the spent dialysate can comeinto contact with each material layer, while each material layer is keptseparate from each of the other layers. One skilled in the art willunderstand that the pouches may be arranged in alternate orders andstill be within the scope of the invention. For example, in anyembodiment of the first or second aspects of the invention, the firstsorbent pouch may contain activated carbon, the second sorbent pouch maycontain alumina and urease, the third sorbent pouch may contain hydrouszirconium oxide, and the fourth sorbent pouch may contain a second layerof alumina. In any embodiment of the first or second aspects of theinvention, the first sorbent pouch may contain activated carbon, thesecond sorbent pouch may contain alumina and urease, the third sorbentpouch may contain a secondary alumina layer and the fourth sorbent pouchmay contain hydrous zirconium oxide. Additionally, any number of sorbentpouches arranged sequentially in the sorbent cartridge is envisioned.

In any embodiment of the first or second aspects of the invention, theurease pouches may be designed so that they can be opened, as shown inFIG. 11a . Top portion 103 of the urease pouch 101 and bottom portion104 of the urease pouch 101 may be connected by a hinge 106 and a latchmember 102. When latch member 102 on the top portion 103 of urease pouch101 is engaged with flange 105 on bottom portion 104 of the urease pouch101, the top portion of the urease pouch 103 can be firmly sealed to thebottom portion of the urease pouch 104. When latch member 102 of theurease pouch 101 is disengaged from flange 105, top portion 103 canpivot on hinge 106 to separate from bottom portion 104. The remainingresidue or material such as alumina within the urease pouch 101 can thenbe removed in order to be discarded or recycled. The urease pouch 101itself may be reused. The urease pouch can be closed as shown in FIG.11b by pivoting the top portion 103 of the urease pouch 101 so that topportion 103 and bottom portion 104 meet, and reengaging latch member 102on the top portion 103 of the urease pouch 101 with flange 105 on thebottom portion 104 of the urease pouch 101. Any type of connectionbetween the top portion 103 and bottom portion 104 of the urease pouch101 is contemplated by the invention. For example, the top portion 103of the urease pouch 101 may include multiple latches (not shown) in theabsence of a hinge member, while the bottom portion 103 of the ureasepouch 101 can include engagement members. When the top portion 103 isplaced onto the bottom portion 104 and twisted, latches can engage theengagement members creating a connection that can be resistant toinadvertent opening. In order for the connection to be broken, the topportion 103 of the urease pouch 101 can be twisted in the oppositedirection, allowing the two portions to separate.

In any embodiment of the first or second aspects of the invention, theurease pouches may be constructed so that they cannot easily be opened.In such embodiments of the first or second aspects of the invention, theurease pouches can be completely sealed to form a complete enclosurearound the sorbent material. During construction of the urease pouch,once the sorbent material is added, the urease pouch can be sealed byany possible means. The urease pouches can be heat sealed to fuse theedges of the urease pouch together. Alternatively, an adhesive may beused to connect the edges together. In embodiments of the first orsecond aspects of the invention where a fiber is used to construct theurease pouches, the edges may be sewn or woven together with a sewnstitch to create a sealed urease pouch. Any type of chemical ormechanical closure to form the urease pouches is contemplated by thisinvention.

In any embodiment of the first or second aspects of the invention, theurease pouches may be made out of rigid material as shown in FIGS. 12aand 12b . The rigid urease pouch 111 can have latch member 112 to allowconnection and detachment of the top portion 113 of the urease pouch 111from the bottom portion 114 of the urease pouch 111. This facilitatesthe recycling or discarding of residue or leftover sorbent material suchas alumina inside the urease pouch 111 while allowing the rigid ureasepouch 111 to be reused. An interior ring or exterior ring 115 may bedisposed inside or around the urease pouch 111, respectively, creatingan additional internal or external sealing member to secure the topportion of the urease pouch 113 to the bottom portion of the ureasepouch 114. The coupled surfaces of the rings may be covered in anadhesive material, or the rings may be attached by any other knowncoupling means. In any embodiment of the first or second aspects of theinvention, the rings may be welded. In any embodiment of the first orsecond aspects of the invention, the rings may be mechanically attachedto the urease pouches such as with rivets, screws or clamps. In anyembodiment of the first or second aspects of the invention, engagementhooks may be placed on the rings, wherein the engagement hooks canattach to the urease pouch in a similar fashion as described forconnecting the top and bottom portions in FIGS. 11a and 11 b.

In FIG. 13, a single urease pouch can contain multiple sorbentmaterials. Urease pouch 121 can comprise a separator 124 within theurease pouch. The separator 124 can run through the entire interiorspace of the urease pouch 121. The separator 124 creates, within theurease pouch 121, a top portion 122 and a bottom portion 123, which arekept completely separate from each other. One sorbent material may beplaced in the top portion of the urease pouch 122, and a differentsorbent material may be placed in the bottom portion of the urease pouch123. This allows two different materials to be placed within a singleurease pouch, but remain separate from one another. In any embodiment ofthe first or second aspects of the invention, two or more sorbentmaterials can be placed in a single urease pouch without a separator.The sorbent materials may be arranged in layers within the urease pouch,or intermixed. The separator 124 can be constructed from the samematerial as the urease pouch itself, or may be a different material thatstill allows fluid to pass through the separator freely, whilepreventing passage of the sorbent material.

In any embodiment of the first or second aspects of the invention, morethan one separator can be used within a single urease pouch. The presentinvention contemplates urease pouches containing 2, 3, 4 or moreseparators within a single urease pouch. In any embodiment of the firstor second aspects of the invention, multiple sorbent materials can bemixed within a urease pouch. Mixing different sorbent materials togethercan be accomplished without a loss in efficiency of the sorbentmaterials.

The urease pouches of the first and second aspects of the invention canhave a mechanism to create a seal between the urease pouch and the innersurface of the sorbent cartridge in which the urease pouch is placed,such that fluid is kept from flowing around the urease pouch and insteadis directed into the urease pouch. FIG. 14 shows one non-limitingembodiment of a seal mechanism of the first and second aspects of theinvention. A flexible urease pouch 131, such as one made out of a fiber,can be placed inside of a sorbent cartridge 132. In any embodiment ofthe first or second aspects of the invention, the urease pouch may bemade out of a rigid material, such as a polymer or metal. In order toavoid a situation where spent dialysate flows around the urease pouchand therefore does not contact the sorbent material inside, the ureasepouch 131 may be sealed to the sorbent cartridge 132. O-ring 133 placedon the circumference of urease pouch 131 can form a seal with thesorbent cartridge 132 so as to prevent spent dialysate from flowingaround the urease pouch 132, and instead through the urease pouch 131.The urease pouch 131 may be filled so that the circumference of theurease pouch 131 is slightly wider than that of the sorbent cartridge132. This will ensure that the urease pouch 131 covers the entire areaof the sorbent cartridge 132 and that there are no spaces for fluid topass by without flowing through the urease pouch 131. O-ring 133 canalso serve to ensure that urease pouch 131 keeps the intended shape byproviding a semi-rigid border.

In any embodiment of the first or second aspects of the invention, asshown in FIG. 15, an elastomeric material 143 may be disposed on theedges of the urease pouch 142. When the urease pouch 142 is placed inthe sorbent cartridge 141, the elastomeric material 143 functions likethe o-ring described above to create a seal and keep liquid from flowingaround the urease pouch 142. The elastomeric material 143 can be made tocompletely cover the outside edges of the urease pouch 141, or theelastomeric material can be disposed in one or more thin strips ofmaterial. Alternatively, in any embodiment of the first or secondaspects of the invention, the inside walls of the sorbent cartridge maybe coated in an elastomeric substance, which will function to form thesame seal when a rigid or semi-rigid urease pouch is placed within. Inany embodiment of the first or second aspects of the invention, theurease pouches may be constructed to be slightly larger than the sorbentcartridge. When the user inserts the urease pouches into the sorbentcartridge, the urease pouch can be compressed slightly to fit in thesorbent cartridge. This will ensure that the urease pouches cover theentire area inside the sorbent cartridge and facilitate the forming of aseal around the edges of the urease pouch.

In any embodiment of the first or second aspects of the invention,ensuring that the urease pouches are properly inserted into the sorbentcartridge may be important. Any method of doing so is contemplated bythis invention. One non-limiting example is shown in FIG. 16. Groove 153may be created in the wall of the sorbent cartridge 152. A key 154, orflange, may be disposed on the side of the urease pouch 151. In orderfor the urease pouch 151 with key 154 to fit within the sorbentcartridge, the key 154 must be aligned with groove 153 in the sorbentcartridge wall. This will ensure that the urease pouch 151 is disposedwithin the sorbent cartridge 152 with the correct alignment. In anyembodiment of the first or second aspects of the invention, optionalridges 155 may be placed within groove 153. The ridges 155 can serve tolock the urease pouch 151 in place vertically within the sorbentcartridge 152. The ridges 155 may be designed so that they are angled onthe top portion of the ridge and flat on the bottom portion of theridge. Once the key 154 passes a ridge 155 in a downward direction, theridge 155 can serve to keep the urease pouch 151 from inadvertentlymoving back upward within the sorbent cartridge.

The ridges 155 may be designed such that the urease pouch 151 may beremoved upward from the sorbent cartridge 152 only with the use of forcegreater than would be expected from inadvertent moving but not so muchforce as to prevent intentionally lifting the urease pouch out of thesorbent cartridge 152. This can be accomplished by using a semi-rigidmaterial as either the key 154, the ridges 155, or both, such that whenenough force is applied the key 154 or ridges 155 can be bent far enoughto allow removal of the urease pouch 151 and then return to theiroriginal shape. Alternatively, the ridges 155 may be attached with aspring mechanism that is connected to a button (not shown), such thatwhen the button is depressed the ridges 155 recede into the interiorwall of the sorbent cartridge 152 and allow easy removal of the ureasepouch 151 from the sorbent cartridge 152.

In any embodiment of the first or second aspects of the invention, theurease pouches may be loosely contained within the sorbent cartridge.The urease pouch need not be made the same size as, or larger than, thesorbent cartridge. One or more urease pouches may be constructed of asmaller size than the sorbent cartridge, and simply placed in thesorbent cartridge.

After construction of the urease pouch containing a sorbent material ormaterials, the material within the urease pouch can be washed so as toremove any particles smaller than the pore or mesh size of the ureasepouch material. This will ensure that all particles within the ureasepouch are large enough so that they cannot inadvertently pass out of theurease pouch. Thus, when used in a sorbent cartridge, the urease pouchesthemselves can act as a particulate filter, ensuring that no particulatematter of the sorbent material, or any other particulate matter, canpass downstream. This may eliminate the need for the use of externalparticulate filters.

In any embodiment of the first or second aspects of the invention,antimicrobial or antibacterial material may be impregnated into theurease pouch. This allows sterilization of the dialysate as thedialysate flows through the sorbent cartridge, and can eliminate theneed for antimicrobial filters. In any embodiment of the first or secondaspects of the invention, medication such as heparin or otheranticoagulants, or antibiotics may be impregnated into the urease pouch.This can allow administration of these medications to the patientwithout the need for adding the drugs to the dialysate.

In any embodiment of the first or second aspects of the invention, flowthroughout the urease pouch can be controlled by variations in theurease pouch material. Generally, fluid moving through a conduit willmove most quickly through the center of the conduit, and more slowlytowards the edges. To ensure that fluid travels more evenly throughoutthe urease pouch, the urease pouch can be constructed such that morefluid enters the urease pouch on the outer edges of the urease pouchthan enters in the center. One non-limiting example is shown in FIG. 17.A urease pouch 161, such as one made out of a fabric, can be constructedwith an extra layer of fabric 162 in the center of the bottom portion ofthe urease pouch 161. This extra layer of fabric 162 effectively reducesthe mesh size of the urease pouch in that location. With a smaller meshsize, resistance to flow will be greater in the center of the ureasepouch 162, and fluid flow will be more evenly distributed to the edgesof the urease pouch 162. In embodiments of the first or second aspectsof the invention where the urease pouch is made out of metal or apolymer, the same effect can be created by making a smaller pore size,or alternatively less pores, in the center of the urease pouch. In anyembodiment of the first or second aspects of the invention, a separator,similar to the one shown in FIG. 13, can be utilized in the middle ofthe urease pouch. The separator can be constructed as described above,such as with an extra layer of fabric near the center, to better controlthe flow of fluid throughout the urease pouch. Although shown in FIG. 17as a centrally positioned rectangular layer, the extra layer of fabric162 or other material may be positioned anywhere along the outer surfaceof the urease pouch 161, and may take any shape, such as circular,rectangular, triangular, etc. such that flow dynamics are altered.

In any embodiment of the first or second aspects of the invention, apatterned flow of fluid through the sorbent cartridge can be created.Occlusions, or blockages, of some of the pores can result in restrictedflow through some portions of the urease pouch. In any embodiment of thefirst or second aspects of the invention, some of the pores in theurease pouch may be larger or smaller than other pores in the rest ofthe urease pouch. Flow will be increased through the larger pores ascompared to the smaller pores, allowing control over fluid flow into andout of the urease pouch.

In any embodiment of the first or second aspects of the invention, themesh size of the urease pouches can be selected based on the need tokeep urease within the pouch. In any embodiment of the first or secondaspects of the invention, water and small dissolved molecules can passthrough the urease pouch. For example, as shown in FIG. 18a , the meshsize of the urease pouch 171 can be such that urease 172 can passthrough the urease pouch material through both the top and the bottom ofthe urease pouch 171, as shown by arrows 173 and 174. A urease pouch 172can be used in embodiments of the first and second aspects of theinvention where an alumina layer or silica layer is provided downstreamof the urease pouch 171, as described herein. The user can place theurease pouch 172 into the sorbent cartridge. Once dissolved, the urease172 can pass out of the urease pouch 171. The urease 172 can beimmobilized by adsorption onto the alumina in the sorbent cartridge,where the urease can be used for dialysis. Because the bottom of theurease pouch is permeable to dissolved urease, the user can inject freshurease into the sorbent cartridge, as explained herein, and the freshurease can still be immobilized by the alumina downstream of the ureasepouch 171. This is because the urease injected can travel through theurease pouch 171 and reach the downstream alumina layer. In anyembodiment of the first or second aspects of the invention, alumina canbe placed within the urease pouch 171 to immobilize urease within theurease pouch. A downstream alumina layer can still be provided to reduceurease migration.

In any embodiment of the first or second aspects of the invention, asshown in FIG. 18b , the top of the urease pouch 181 can be made with amesh size that does not allow dissolved urease to pass through theurease pouch 181, as shown by arrow 184, while the bottom of the ureasepouch 181 can be made with a mesh size that does allow dissolved ureaseto pass into the urease pouch 181, as shown by arrow 183. In embodimentsof the first and second aspects of the invention, such as the one shownin FIG. 18b , the urease 182 can enter the urease pouch 181 through thebottom of the urease pouch 181, but cannot exit through the top of theurease pouch 181. In order to replenish the urease in the sorbentcartridge, a new urease pouch 181 can be added to the system. Alumina isnot necessary, because the urease 182 is immobilized, and unable to exitthrough the top of the urease pouch 181. In any embodiment of the firstor second aspects of the invention using a urease pouch 181 as shown inFIG. 18b , a layer of alumina can still be provided in the urease pouch181 or downstream of the urease pouch 181 in order to reduce ureasemigration. Urease introduced through an injection port as describedherein can be used to replenish the urease when using a urease pouch181. The urease solution that is injected can enter the urease pouch 181through the bottom of the urease pouch 181, where the urease will beimmobilized because the urease cannot exit the urease pouch 181.

In any embodiment of the first or second aspects of the invention, asshown in FIG. 18c , both the top layer and the bottom layer of theurease pouch 191 can be made with a mesh size small enough not to allowurease to pass through the urease pouch 191, as shown by arrows 193 and194. Water and small molecules, such as urea, can still pass through theurease pouch 191 to react with the urease 192 within the urease pouch191. In embodiments of the first or second aspects of the inventionusing a urease pouch 191 as shown in FIG. 18c , the urease 192 will besubstantially retained within the urease pouch 191. Because the urease192 cannot exit through the urease pouch 191, alumina may not benecessary for immobilization of the urease 192. However, a separatealumina layer can, in any embodiment of the first or second aspects ofthe invention, be used in order to prevent urease migration. In order toreplenish the urease within the sorbent cartridge, a new urease pouch192 can be added as explained herein.

One skilled in the art will understand that various combinations and/ormodifications and variations can be made in the dialysis systemdepending upon the specific needs for operation. Moreover featuresillustrated or described as being part of an aspect of the invention maybe included in the aspect of the invention, either alone or incombination.

1-16. (canceled)
 17. A method, comprising the steps of: adding eithersolid urease or urease solution to a sorbent cartridge adapted toreplenish urease in the sorbent cartridge.
 18. The method of claim 17,wherein the step of adding the solid urease comprises the steps ofremoving a urease pouch having a reduced amount of urease, if present,and then adding a fresh urease pouch into the sorbent cartridge.
 19. Themethod of claim 17, wherein the step of adding the urease solutioncomprises introducing a urease solution into the sorbent cartridgehaving a concentration between any of 1 mg/mL to 250 mg/mL, 15 mg/mL to150 mg/mL, 10 mg/mL to 100 mg/mL, or 75 mg/mL to 250 mg/mL of urease.20. The method of claim 17, further comprising the step of either:recharging an amount of one or more sorbent materials contained in thesorbent cartridge by passing a solution containing an appropriate amountof solutes for recharging the one or more sorbent materials through thesorbent cartridge; or recharging an amount of one or more sorbentmaterials by replacing one or more modules of a modular regenerationassembly containing an amount of the one or more of sorbent materials.